At present, cancer is still a leading cause of mortality and morbidity throughout the world. Conventional cancer therapies include surgery, chemotherapy and radiotherapy. Despite healthcare improvements, many tumors remain unresponsive to traditional therapy, and thus investigation for a new modality of treatment has been urgently expected.
Mesenchymal stem cells (MSCs) were first discovered in the bone marrow in 1960s (Friedenstein et al., (1966) J. Embryol. Exp. Morphol. 16: 381-390; Friedenstein et al., (1968) Transplantation 6: 230-247) and were first considered as stem cells by Caplan and named mesenchymal stem cells in 1991 (Caplan A. I., J. Orthop. Res. 9: 641-650). MSCs were also the first type of stem cells utilized in clinical regenerative medicine due to their attractive features such as easy isolation, rapid ex vivo expansion, feasibility of autologous transplantation and their powerful paracrine function (Gregory et al., (2005) Sci. STKE 294: pe37). Recently it has been shown that bone marrow-derived stem cells (BMSCs) are able to migrate specifically to tumor cells in vitro using transwell migration assays (Loebinger et al., (2009) Cancer Res. 69: 4134-442; Nakamizo et al., (2005) Cancer Res. 65: 3307-3318; Menon et al., (2007) Stem Cells 25: 520-528; Xin et al., (2007) Stem Cells 25: 1618-1626) and in vivo using animal tumor models (Studeny et al., (2002) Cancer Res. 62: 3603-3608; Studeny et al., (2004) J. Natl. Cancer Inst. 96: 1593-1603; Khakoo et al., (2006) J. Exp. Med. 203: 1235-1247; Wang et al., (2009) Stem Cells 27(7): 1548-1558) although the specific molecular mechanisms are not understood. This tumor-directed migration and incorporation of MSCs makes them promising cell-based delivery vehicles for cancer therapy. By combining with anticancer genes, utilization of engineered MSCs has inspired an efficient approach for cancer therapy (Loebinger et al., (2009) Cancer Res. 69: 4134-442; Xin et al., (2007) Stem Cells 25: 1618-1626; Ren et al., (2008) Stem Cells 26: 2332-2338; Ren et al., (2008) Gene Ther. 15: 1446-1453; Kanehira et al., (2007) Cancer Gene Ther. 14: 894-903).
Tumor necrosis factor (TNF, formerly referred to as TNF-alpha (TNFα)) is a cytokine with well-known anticancer properties and is being utilized as an agent for the treatment of patients with locally advanced solid tumors (Tomita et al., (1998) Anticancer Res. 18: 3937-3939). However, clinical applications of TNFα for cancer therapy are still limited because TNF has been found to have toxic side effects, such as fever and decreased blood pressure similar to endotoxin-like shock, before therapeutic doses can be reached (Wang et al., (2006) Protein Expr. Purif. 45: 60-65). TNF has been applied to treatment of cancer for decades. Study on potential mechanisms underlying the variability in cell sensitivity to TNF-driven cytotoxicity is continuing so as to develop novel methods for enhancing TNF anticancer properties and minimizing side effects. Deleting domains of TNF responsible for causing systemic toxicity is one of several strategies (Gerspach et al., (2009) Biofactors 35: 364-372). Making TNF mutants selectively binding to TNFR was previously reported (Ameloot & Brouckaert (2004) Methods Mol. Med. 98: 33-46; Novakovic et al., (1997) Cytokine 9: 597-604). Other strategies included interfering with the NFkB Pathway (Zwacka et al., (2000) J. Gene Med. 2: 334-343; Wang et al., (1999) Nat. Med. 5: 412-417), co-administration of inhibitor of Nitric Oxide Synthase (NOS) (de Wilt et at, (2000) Br. J. Cancer 83: 1176-1182), changing the administration route of TNF alone or in combination with conventional drugs to enhance the delivery efficiency of TNF or conventional drugs (Bartlett et al., (1998) Cancer 83: 1251-1261) and gene therapy that achieves selective intra-tumoral TNF expression by utilizing radiation-induced activation of viral vectors (Weichselbaum et al., (2002) Lancet Oncol. 3: 665-671). There remains, therefore, an on-going need for more effective and targeted application of TNF directed against tumor cells and with reduced side-effects seen with generalized administration of TNF to a patient.